Multiple myeloma (MM) patients suffer from various treatment-related symptoms, including neuropathic pain, fatigue, decreased appetite and sleep disturbance, causing significant distress and treatment delays. Although newer drugs used for treatment of MM exhibit immunomodulatory properties, none of them reported to suppress inflammatory markers in patients. Symptoms, such as neuropathic pain, are highly prevalent in treated patients. The link between these symptoms and increases in specific proinflammatory cytokines, primarily interleukin (IL)-i, IL-6, and tumor necrosis factor (TNF)-a, is well-recognized. We theorize that many of these symptoms are related to cytokine dysegulation produced by both disease and treatment. Thus the goal of this project is to test the hypothesis that the transcription factor NF-kB, which controls the expression of proinflammatory cytokines, is the driving force in producing a cluster of symptoms in patients with MM. We developed this central hypothesis based on animal models of sickness behavior which demonstrate that IL-i, IL-6, and TNF-a, drive components of sickness in animals (anorexia, disturbed sleep, hyperalgesia, disrupted learning). The activation of NF-kB can lead to expression of inflammatory cytokines to the brain via leaky regions in the blood-brain barrier, or active transport of molecules and afferent nerve fibers. Downregulation of specific cytokines through inhibition of NF-kB activation offers a novel opportunity for reducing symptom burden associated with disease and its treatment. Numerous studies from our laboratory and others indicate that curcumin (diferuloylmethane), a component of turmeric, can suppress the NF-kB activation pathway leading to reduced expression of proinflammatory cytokines. Curcumin is well-tolerated in humans, making it an ideal supportive care candidate. That curcumin can modulate neuropathic pain, fatigue, depression and cognitive slowing has been reported in various rodent models. Thus Project 2 will examine whether or not the inhibition of NF-kB activation by curcumin will downregulate inflammatory cytokine expression and thus improve disease and treatment related symptoms. We will: (i) Determine whether curcumin can modulate the effect of MM therapies on NF-kB activation and symptom-related NF-kB-regulated inflammatory cytokines (TNF, IL-i, IL-6) expression in multiple myeloma cell lines, and in animal models of MM, and (2) In a placebo controlled clinical trial, determine whether curcumin can modulate the effects of thalidomide during maintenance therapy, on NF-kB activation and NF-kB-regulated inflammatory cytokines expression in multiple myeloma patients leading to improvement of symptoms. Overall, these studies will establish the role of NF-KB and NFKB- regulated gene products in inflammation-induced symptoms in MM patients, and examine the effectiveness of curcumin in symptom reduction.